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December 2001
Vol. 4, No. 12, pp 12.
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Light splicing DNA
figure: energy-minimized model of PQ3
Pulling together. Energy-minimized model of PQ3 intercalated within a triple helix. The oligopyrimidine and oligopurine strands of the Watson–Crick double helix are blue and red, respectively, and the third oligonucleotide strand is yellow. J. AM. CHEM. SOC. 2001, 123, 9283–9292.
Large enzymes are not the only means to site-directed nucleic acid cleavage (see “Directing RNase H”), and scientists from Paris’s Collège de France and Muséum National d’Histoire Naturelle have recently used a small photoactive molecule that can intercalate within a DNA helix and slice DNA strands with precision.

DNA photocleavage occurs by excitation of the intercalating compound, which forms an excited-state species that can inflict fatal redox damage on base pairs. But this mechanism does not directly translate into sequence-specific targeting. So when the French researchers sought to accomplish directed cleavage of HIV-1 DNA, they also took the approach of including a free oligonucleotide in the mix as a sequence-specific DNA-binding ligand (J. Am. Chem. Soc. 2001, 123, 9283–9292).

Amino-p-quinacridines are polyheterocyclic aromatic compounds that strongly stabilize the formation of triple-helix nucleotide structures and have an electronic structure favorable to DNA redox chemistry. With these properties in mind, the researchers performed irradiation experiments on a particularly active quinacridine, denoted PQ3, with HIV DNA and an oligonucleotide that is complementary to a short proviral target tract of the sequence. In repeated experiments, the scientists observed selective cleavage of four base-pair positions within a five-pair area, both when PQ3 and the oligonucleotide were added as separate components and as a preformed conjugate, but no directed cleavage when free oligonucleotide was not included.

Therefore, it seems that PQ3 strongly favors helical binding, and thus photocleavage, within a triplex structure that locks into a specific location. It is important to point out, however, that the DNA damage did not take place within the triplex area but on GC pairs 6–10 bases, in one direction, away from this segment. Because it is clear that PQ3 binds to the oligonucleotide, this points to the occurrence of an electron-transfer mechanism, that is, guanines are oxidized by electron migration through the helix to a PQ3 orbital. It is not completely clear why the damage was limited to only one direction from the triplex segment and why it did not affect GC pairs more than 10 bases away. Investigations into such topics may lead to a targeted and tunable viral, or tumor, treatment method, not to mention a means to further elucidate some of the basic functioning of DNA.

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